• Journal of Pharmaceutical Investigation
• /
• v.31 no.3
• /
• pp.167-172
• /
• 2001

All-trans retinoic acid (ATRA), vitamin A acid, has been shown to exert anticancer activity in a number of types of cancers, particularly in acute promyelocytic leukaemia (APL). Due to its highly variable bioavailability and induction of its own metabolism after oral treatment, development of parenteral dosage forms are required. However, its poor aqueous solubility and chemical unstability give major drawbacks in parenteral administration. This study was undertaken to investigate a possibility to develop a parenteral formulation of ATRA by employing solid lipid nanoparticle (SLN) as a carrier. By optimizing the production parameters and the composition of SLNs, SLNs with desired mean particle size (<100 nm) as a parenteral dosage form could be produced from trimyristin (as solid lipid), Egg phosphatidylcholine and Tween 80 (as SLN stabilizer). The mean particle size of SLN formulation of ATRA was not changed during storage, suggesting its physical stability. Thermal analysis confirmed that the inner lipid core of SLNs exist at solid state. The mean particle size of ATRA-loaded SLNs was not significantly changed by the lyophilization process. ATRA could be efficiently loaded in SLNs, while maintaining its anticancer activity against HL-60, a well-known APL cell line. Furthermore, by lyophilization, ATRA loaded in SLN could be retained chemically stable during storage. Taken together, our present study demonstrates that physically and chemically stable ATRA formulation adequate for parenteral administration could be obtained by employing SLN technology.

• YAKHAK HOEJI
• /
• v.54 no.4
• /
• pp.244-251
• /
• 2010

Standardized parenteral nutrition is required to improve patient's safety, clinical appropriateness and to increase uniformity between institution and institutions. We assessed the consistency with the American society for parenteral and enteral nutrition (A.S.P.E.N.) practice guideline for PN by evaluating current practice process for parenteral nutrition formulation in inpatients pharmacies in Korea. Each question in this survey was based on 2007 A.S.P.E.N. recommendations of standard parenteral nutrition formulation, the American society of health-system pharmacists (ASHP), and the United State Pharmacopoeia (USP) Chapter 797 guideline for compounding parenteral nutritions. All 90 Korean society of hospital pharmacist (KSHP) member directors of pharmacy were requested to respond to the survey in order to compare the survey results to ASHP national survey of pharmacy practice in hospital settings (2002) in compliance with A.S.P.E.N. guideline. We had final response rate of 35.6%. 25 (100%) hospitals complied with this Garb guideline (response rate was 84.4%) which was the highest compliance. Only 17.9% of hospital pharmacies were actively involved in complications monitoring. Monitoring complications and efficacy were least in compliance with the A.S.P.E.N. guideline. 69.0% of Korean pharmacists adjusted medication dosage based on disease state or monitoring laboratory data in compliance with the A.S.P.E.N. guideline. Over 50% of the hospital pharmacies failed to provide and evaluate staff training in aseptic manipulation skills periodically. Korean hospital pharmacies need to comply with the standard practice guideline for compounding sterile preparation in order to provide better quality of parenteral nutrition service for specific patient population.

• Archives of Pharmacal Research
• /
• v.28 no.12
• /
• pp.1400-1404
• /
• 2005

The aim of the present study was to develop the aqueous parenteral formulation containing propofol using o/w microemulsion systems. Propofol itself was chosen as the oil phase and its content was fixed to 1$\%$, w/w. Pseudoternary phase diagrams were constructed to obtain the concentration range of surfactant and cosurfacatnt and the optimum ratio between them for microemulsion formation. Consequently, the suitability of the chosen microemulsion system as a parenteral formulation was evaluated from the stability and hemolysis tests on that. Among the surfactants and cosurfactants screened, the mixture of Solutol HS 15-ethyl alcohol (5/1) showed the largest o/w mocroemulsion region in the phase diagram. When 1 $\%$ (w/w) of propofol was solubilized with 8$\%$ (w/w) of Solutol $HS^{circledR}$??? 15-ethyl alcohol (5/1), the average droplet size (150 nm) and the content of propofol in the systems were not significantly changed at 40$^{circ}C$ for 8 weeks. The hemolysis test showed that this formulation was nontoxic to red blood cells. In conclusion, propofol was successfully solubilized with the o/w microemulsion systems.

• Journal of Pharmaceutical Investigation
• /
• v.40 no.spc
• /
• pp.83-95
• /
• 2010

Over the years, nanoparticle drug delivery systems have demonstrated versatile potentials in biological, medical and pharmaceutical applications. In the pharmaceutical industry nanotechnology research has mainly focused on providing controlled drug release, targeting their delivery to specific organs, and developing parenteral formulations for poorly water soluble drugs to improve their bioavailability. Achievement in polymer industry has generated numerous polymers applicable to designing nanoparticles. From viewpoints of product development, a nanocarrier material should meet requirements for biodegradability, biocompatibility, availability, and regulatory approval crieteria. Albumin is indeed a material that fulfills such requirements. Also, the commercialization of a first albumin-bound paclitaxel nanoparticle product (Abraxane$^{TM}$) has sparked renewed interests in the application of albumin in the development of nanoparticle formulations. This paper reviews the intrinsic properties of albumin, its suitability as a nanocarrier material, and albumin-based parenteral formulation approaches. Particularly discussed in detail are albumin-based particulate injectables such as Abraxane$^{TM}$. Information on key roles of albumin in the nab$^{TM}$ technology and representative manufacturing processes of albumin particulate products are provided. It is likely that albumin-based particulate technology would extend its applications in delivering drugs, polypeptides, proteins, vaccines, nucleic acids, and genes.

• YAKHAK HOEJI
• /
• v.41 no.5
• /
• pp.607-614
• /
• 1997

Flurbiprofen- and flurbiprofen axetil-loaded microemulsions composed of soybean oil, poloxamer 407, glycerine and water were prepared by generator-type homgenizer and ultrasoni c probe system. The particle size of microemulsions was measured by the dynamic light scattering method. The pharmacokinetics and organ distribution of flurbiprofen were investigated after intravenous injection of flurbiprofen solution, flurbiprofen-loaded microemulsion and flurbiprofen axetil-loaded microemulsions equivalent to 10mg/kg of flurbiprofen to rats. Blood samples were collected from the anterior ciliary artery of rats for 24hr, and flurbiprofen in plasma and organs was analyzed by HPLC. Stable microemulsions were prepared. Even though there is a little change in droplet size just after the preparation, no creaming and no separation were occured during the storage period for 6 months at 4, 21, 37 and 45$^{\circ}C$. Pharmacokinetic parameters and organ distribution of flurbiprofen after intravenous injection of flurbiprofen- and flurbiprofen axetil-loaded microemulsions emulsified with poloxamer 407 were not significantly different from those of commercial lipid microemulsion emulsified with lecithin. Therefore, it is concluded that flurbiprofen- and flurbiprofen axetil-loaded microemulsion prepared with poloxamer 407 could be used as a parenteral formulation.

• YAKHAK HOEJI
• /
• v.49 no.4
• /
• pp.268-274
• /
• 2005

Paclitaxel is an effective antineoplastic agent against ovarian, colon and breast tumors. But there have been many difficulties to formulate this drug due to the extremely low aqueous solubility. Paclitaxel is currently formulated in a vehicle composed of Cremophor EL and absolute ethanol mixture which is $5\~20$ fold diluted in normal saline or $5\%$ dextrose solution before I.V. injection. However, this formulation has many problems such as allergic reactions and drug precipitation on aqueous dilution. To overcome these problems, we prepared the micelle and microemulsion systems for parenteral administration of paclitaxel by using glycofurol, $Soluto^{(R)}lHS$ 15 and oleic acid. Phase diagram, pH-rate stability, particle size distributions and pharmacokinetics of the systems were studied. Micelles and microemulsions formulated as nano-particle delivery system were physically and chemically stable. Therefore, these formulations might be the promising alternative candidate for the parenteral delivery of paclitaxel.

• Journal of Pharmaceutical Investigation
• /
• v.31 no.3
• /
• pp.151-160
• /
• 2001

The purpose of this study is to investigate the interaction of progesterone with various cyclodextrins (CDs) in the aqueous solution and in solid state, and finally to formulate a parenteral aqueous formulation. CDs used were ${\alpha}-$, ${\beta}-$, and ${\gamma}-CD$, $2-hydroxypropyl-{\beta}-CD$ (HPCD), sulfobutyl $ether-{\beta}-CD$ (SBCD), $dimethyl-{\beta}-CD$ (DMCD) and $trimethyl-{\beta}-CD$ (TMCD). The solubility studies of progesterone were performed in the presence of various CDs as a function of concentration or temperature. The solubility of progesterone increased in the rank order of ${\alpha}-CD$ < ${\beta}-CD$ < ${\gamma}-CD$ < TMCD$ < HPCD < DMCD < SBCD. Addition of SBCD (200 mg/ml) in water increased the aqueous solubility $(9.36\;{\mu}g/ml)$ about 3,200 times, and lowering the temperature facilitated the solubilization of progesterone. However, the addition of HPCD and SBCD in 20:80 (v/v) polyethylene glycol 300-water and propylene glycol-water cosolvents markedly decreased the solubility of progesterone, compared with solubilizing effects in water. Physical mixtures and solid dispersions of progesterone with HPCD or SBCD were prepared, and evaluated by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), near IR spectroscopy and dissolution studies. By DSC and IR studies, it was found that progesterone was dispersed in HPCD in monotectic state and dissolved rapidly from both solid dispersions. Based on solubility studies, new aqueous progesterone fonnulations (5 mg/ml) containing SBCD (200 mg/ml) could be prepared and did not form precipitates even after 2 months at $4^{\circ}C$. The solution was transparent when mixed with normal saline and 5% dextrose injection at 1: 1, 1:10 and 1:20 (v/v) even after 7 days. Permeation rates of progesterone through a cellulose membrane from 20% PEG 300 solution $(50\;{\mu}g/ml)$ containing HPCD or SBCD were compared with oily formulation. Permeation of progesterone from oily formulation did not occur up to 8 hr, but aqueous formulations showed fast permeation rates from early stage of permeation study. The addition of HPCD or SBCD retarded the permeation rates of progesterone with the increase of CD concentrations, suggesting the possibility of a controlled absorption from the site administered intramuscularly. These results demonstrate that it is feasible to develop a new progesterone parenteral aqueous injection (5 mg/ml) using SBCD.

• Biomolecules & Therapeutics
• /
• v.17 no.1
• /
• pp.104-110
• /
• 2009

Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations in the phenylalanine catabolic enzyme, phenylalanine hydroxylase (PAH). The use of phenylalanine ammonia-lase (PAL) by oral and parenteral routes as a therapeutic drug for PKU has been severely limited due to inactivation by intestinal proteolysis and immune reactions. PEGylation was applied to PAL to reduce the degrees of antigenicity and proteolytic inactivation. Kinetic experiments with native PAL and pegylated PALs were performed, and pH stability, temperature stability, and protease susceptibility were evaluated. Enzyme linked immunosorbent assay (ELISA) was carried out to measure the immune complex between pegylated PALs and antiserum that had been extracted from a PAL-immunized mouse. Pegylated PAL, especially branched pegylated PAL (10 kDa, 1:32), was more active for phenylalanine and more stable in pancreatic proteases than native PAL. Native PAL was optimal at pH 8.5, corresponding to the average pH range of the small intestine; the same finding was noted for pegylated PALs. All linear and branched pegylated PALs had low reactivity with mouse antiserum, especially the 1:16 formulation with linear 5-kDa PEG and the 1:32 formulation with branched 10-kDa PEG. Therefore, we suggest the 1:32 formulation with branched 10-kDa PEG as the most promising formulation for enzyme replacement therapy.

• Archives of Pharmacal Research
• /
• v.23 no.4
• /
• pp.385-390
• /
• 2000

To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA) microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method. Methylene chloride or ethyl acetate was applied as an organic phase and poly(vinyl alcohol) as a secondary emulsion stabilizer. Low loading efficiencies of less than 20％ were observed and the in vitro release of OVA showed a burst effect in all batches of different microspheres, followed by a gradual release over the next 6 weeks. Formulation processes affected the size and morphology, drug content, and the controlled release of OVA from PLGA microspheres.

• Journal of Pharmaceutical Investigation
• /
• v.40 no.spc
• /
• pp.33-43
• /
• 2010

Hyaluronic acid (HA) is a biodegradable, biocompatible, non-toxic, non-immunogenic and non-inflammatory linear polysaccharide, which has been used for various medical applications including arthritis treatment, wound healing, ocular surgery, and tissue augmentation. Because of its mucoadhesive property and safety, HA has received much attention as a tool for drug delivery system development. It has been used as a drug delivery carrier in both nonparenteral and parenteral routes. The nonparenteral application includes the ocular and nasal delivery systems. On the other hand, its use in parenteral systems has been considered important as in the case of sustained release formulation of protein drugs through subcutaneous injection. Particles and hydrogels by various methods using HA and HA derivatives as well as by conjugation with other polymer have been the focus of many studies. Furthermore, the affinity of HA to the CD44 receptor which is overexpressed in various tumor cells makes HA an important means of cancer targeted drug delivery. Current trends and development of HA as a tool for drug delivery will be outlined in this review.